Late-stage diagnosis: The driving force behind high breast cancer mortality in Ethiopia: A systematic review and meta-analysis

Introduction Breast cancer continues to be the most common malignancy and the leading cause of cancer-related deaths in Ethiopia. The poor prognosis and high mortality rate of breast cancer patients in the country are largely caused by late-stage diagnosis. Hence, understanding the epidemiology of late-stage diagnosis is essential to address this important problem. However, previous reports in Ethiopia indicated inconsistent findings. Therefore, this literature review was conducted to generate dependable evidence by summarizing the prevalence and determinants of late-stage diagnosis among breast cancer patients in Ethiopia. Methods Pertinent articles were retrieved by systematically searching on major electronic databases and gray literature. Data were extracted into an Excel spreadsheet and analyzed using the STATA 17 statistical software. The pooled estimates were summarized using the random effect meta-analysis model. Heterogeneity and small study effect were evaluated using the I2 statistics and Egger’s regression test in conjunction with the funnel plot, respectively. Meta-regression, sub-group analysis, and sensitivity analysis were also employed. Protocol registration number: CRD42024496237. Results The pooled prevalence of late-stage diagnosis after combining reports of 24 studies with 8,677 participants was 65.85 (95% CI: 58.38, 73.32). Residence (adjusted OR: 1.92; 95% CI: 1.45, 2.53), patient delay at their first presentation (adjusted OR: 2.65; 95% CI: 1.56, 4.49), traditional medicine use (adjusted OR: 2.54; 95% CI: 1.89, 3.41), and breast self-examination practice (adjusted OR: 0.28; 95% CI: 0.09, 0.88) were significant determinants of late-stage diagnosis. Conclusion Two-thirds of breast cancer patients in Ethiopia were diagnosed at an advanced stage. Residence, delay in the first presentation, traditional medicine use, and breast self-examination practice were significantly associated with late-stage diagnosis. Public education about breast cancer and its early detection techniques is crucial to reduce mortality and improve the survival of patients. Besides, improving access to cancer screening services is useful to tackle the disease at its curable stages.


Introduction
Breast cancer is the world's most common cancer in women with an estimated 2.3 million incident cases and 685,000 deaths in 2020 alone [1,2].During the same year, the Sub-Saharan region contributed the highest incidence and mortality of breast cancer with 1,109,209 cases and 25,626 deaths, which makes it one of the major public health issues in the area [2].In Ethiopia, breast cancer is the leading malignancy, accounting for about one-third of all cancer cases among women [3].Annually, an estimated 16,133 new breast cancer cases and 9061 deaths occur in the country [4].
The World Health Organization (WHO) inaugurated the Global Breast Cancer Initiative (GBCI) aiming to reduce global breast cancer mortality by 2.5% per year and prevent 2.5 million breast cancer deaths worldwide between 2020 and 2040 [5].To achieve these goals, WHO urged to have early diagnosis and treatment of breast cancer, but recent data shows that most breast cancer patients are diagnosed at a late stage [6,7].
Late-stage diagnosis has multifaceted consequences that affect the patients, their families and the community at large [8,9].Stage at diagnosis is an important predictor of survival; latestage diagnosis increases the mortality risk by more than 82% [10,11].Patients diagnosed at an advanced stage also had a higher risk of recurrence and poor prognosis [12,13].Besides, latestage diagnosis is also associated with poor quality of life, increased healthcare costs and treatment-related problems [8,14].
According to different studies, late-stage breast cancer diagnosis is associated with a low level of awareness about the disease and its screening, poor facilities for accurate and timely diagnosis and treatment, negative symptom interpretation, fear, consideration of traditional healing, and lack of trust and poor access to healthcare [9,[15][16][17].
In Ethiopia, cancer care is pioneered by the only oncology and cancer referral center (Black Lion Specialized Hospital, which is found in the national capital (Addis Ababa) and is providing services for the majority of cancer cases from all over the country [18].However, recently, Hospitals in different regions of the country are inaugurating cancer care, and this may enhance access; hence, promoting early diagnosis.Previously, various studies have been conducted and found a widely varying prevalence of late-stage breast cancer diagnosis and identified different factors associated with late presentation in different parts of the country [7,[19][20][21][22].However, summarized national evidence about the prevalence and determents of latestage diagnosis among breast cancer patients is lacking.Thus, in this analysis, we aimed to assess the pooled prevalence and determinants of late-stage diagnosis among breast cancer patients in Ethiopia.

Study protocol registration and reporting
This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database with protocol number: CRD42024496237.The findings of this review are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [23], (S1 Checklist).

Information source and search strategy
Relevant articles were retrieved by conducting a comprehensive web-based search on PubMed, Scopus, EMBASE, African Journals Online (AJOL), Hinari, Epistemonikos, CINAHL, and Cochrane Library.Additionally, other gray literature sources like Google Scholar and online repositories of Ethiopian universities were examined.The reference lists of pertinent studies were also scrutinized to identify additional reports.Two members of the review team (HG and MBS) searched the databases independently from December 1 to 26, 2023.The database search was conducted using the following keywords: "delayed diagnosis" OR "late-stage diagnosis" OR "advanced stage diagnosis" OR "delayed presentation" OR "advanced stage presentation" OR "end-stage diagnosis" OR "stage at diagnosis" OR stage AND "breast cancer" OR "mammary cancer" OR "breast tumor" OR "breast neoplasm" OR "breast carcinoma" OR "breast malignancy" AND Ethiopia.

Eligibility criteria
The eligibility criteria for this review were based on CoCoPop (condition, context, and population) mnemonic [24].Correspondingly, all primary studies published in the English language and reported the number and/or prevalence and/or associated factors of late-stage diagnosis among breast cancer patients in Ethiopia and fulfill the following criteria (Table 1).were included in this review.
All studies that fulfilled the aforementioned criteria and clearly described that staging was conducted at the time of diagnosis were considered in this analysis.No consideration was given to the time period of publication.Nevertheless, duplicate studies, abstracts without full text and qualitative studies without outcome of interest were excluded from this analysis.Exclusive electronic request messages were sent to authors for full articles not available online or to clarify data.

Outcome measurement
This systematic review had two major outcomes.The primary outcome was the prevalence of late-stage diagnosis among breast cancer patients in Ethiopia.The secondary outcome of this analysis was to identify factors associated with late-stage diagnosis of breast cancer patients in Ethiopia.Late-stage or advanced-stage breast cancer: breast cancer diagnosed at stage III or stage IV, irrespective of the staging being clinical or pathological [25,26].
Early-stage breast cancer: breast cancer diagnosed at stage I or stage II [6,26].Patient presentation delay: is the time from the patient's first detection of the first symptom/breast abnormality until their first healthcare facility visit and it was categorized as �3 months (long presentation delay) and <3 months (short delay) [20,27].

Study identification, quality assessment, and data extraction
Records identified through the electronic database search were exported to a reference management software (Endnote version X7.2), where duplicate entries were eliminated.The remaining articles were then assessed by title and abstract.For articles found to be pertinent by title and abstract, a full-text review against the specified inclusion/exclusion criteria was conducted to identify potential articles to be included in this review.
To evaluate the quality of the studies, we utilized the Joanna Brigg's Institute (JBI) quality assessment checklist [28].Two authors of the review (HG and EBG) independently evaluated the quality of each study and inconsistencies were resolved by involving a third author (MBS).
Records of primary studies were abstracted into a standard data extraction, Excel spreadsheet form that was developed by considering the JBI guide for data extraction and synthesis [29].Two authors of the review extracted the data independently and inconsistencies were resolved by discussion.Extracted data include last name of the first author and year of publication, study area, sample size and number and/or prevalence of late-stage diagnosis.Besides, data about predictors of late-stage diagnosis were also abstracted in the form of a two-by-two table.

Data management and analysis
The necessary data were extracted into Excel spreadsheet and then exported to the STATA version 17 software for further statistical analysis.The general features of primary studies are described in tables.The prevalence and its respective standard error in each primary study were considered to compute the pooled prevalence estimates.The pooled odds ratio estimates were computed after extracting the necessary data into a two-by-two table format.The random effects model was employed to estimate the pooled effect size, and estimates were depicted by forest plots.Heterogeneity among included reports was evaluated using the I 2 statistics and it was considered as high, moderate, or low when I 2 test statistics results were 75%, 50%, and 25% respectively [30].Subgroup analysis was conducted to further investigate the potential source of heterogeneity considering the study area, study design and data collection methods of primary studies.Funnel plot and Eggers regression test were used to assess publication bias, and Eggers regression test with a p-value less than 0.05 was considered to indicate the presence of publication bias [31].The observed substantial heterogeneity between included studies was also further explored by subgroup analysis.Besides, the impact of each study on the overall estimate was investigated using a leave-one-out sensitivity analysis.

Ethics approval and consent to participants
Not applicable because no primary data were collected.

Identification of records
A total of 554 primary studies were retrieved through the combined electronic literature search.Of these, 182 records were removed due to duplication.Assessment of the title and abstract of the remaining records eliminated 337 studies.Then, the full texts of 35 records were evaluated against the eligibility criteria, and 25 were included in the meta-analysis (Fig 1).

Prevalence of late-stage diagnosis
After combining the findings of 24 studies with a total of 8,677 participants, the pooled prevalence of late-stage diagnosis among breast cancer patients in Ethiopia was 65.85 (95% CI: 58.38, 73.32) (Fig 2).

Heterogeneity, publication bias and sensitivity analysis
A substantial level of heterogeneity (I 2 = 98.42%) was observed between included studies; for that, the pooled prevalence estimate was computed using the random effect model (DerSimonian-Laird method), in order to take this significant heterogeneity into account.Subgroup analysis was also done based on study area, study design and method of data collection, yet, no significant variation was detected.Besides, the random effect meta-regression was performed to further explore the source of heterogeneity by considering sample size and publication year as covariates.Consequently, the results indicated that sample size and year of publication had no effect on heterogeneity between studies (Table 3).Publication bias was evaluated using a funnel plot and Egger's regression test.As a result, findings of both the funnel plot (Fig 3).and Egger's regression test (p = 0.95) indicated no evidence of publication bias.Furthermore, the influence of each study on the overall prevalence estimate was investigated using a leave-one-out sensitivity analysis.As a result, the pooled estimates of late-stage diagnosis among breast cancer patients in Ethiopia was steady and reliable when analyzed by removing one study at a time (Fig 4).

Determinants of late-stage diagnosis
Data about 7 variables (educational status, marital status, residence, patient delay, utilization of traditional medicine, family history of breast cancer, and breast self-examination) were extracted into an Excel spreadsheet in the form of a two-by-two table and analyzed separately.Consequently, residence, patient delay, traditional medicine utilization and breast self-examination were found to have a statistically significant association with late-stage diagnosis of breast cancer.In this regard, the risk of late-stage diagnosis was 92% higher among rural residents when compared to urban dwellers (adjusted OR: 1.92; 95% CI: 1.45, 2.53).The odds of late-stage diagnosis were 2.65 times more likely among breast cancer patients who had experienced patient delay during their first presentation as compared to their counterparts (adjusted OR: 2.65; 95% CI: 1.56, 4.49).Similarly, patients who had utilized traditional medicine had a 2.54 times higher risk of late-stage diagnosis relative to their counterparts (adjusted OR: 2.54; 95% CI: 1.89, 3.41).The findings of our analysis also indicated that practicing breast self-examination reduces the risk of late-stage diagnosis by 72% (adjusted OR: 0.28; 95% CI: 0.09, 0.88) (Table 4).Conversely, pooling the effect size of some variables deemed meaningless because of the difference in categorization across primary studies.For instance, five studies explored the association between age and late stage diagnosis; however, the effect size was not pooled because all of the studies categorized age inconsistently.

Discussion
Breast cancer continued to be the most common malignancy and the leading cause of cancerrelated deaths in Ethiopia [2].Late-stage diagnosis significantly contributes to the poor prognosis and high mortality of breast cancer patients [43,48].In Ethiopia, evidence about the epidemiology of late-stage diagnosis among breast cancer patients is not conclusive.Therefore, we aimed to determine the pooled prevalence and determinants of late-stage diagnosis among breast cancer patients in Ethiopia.
In this study, the pooled prevalence of late-stage diagnosis among breast cancer patients in Ethiopia was 65.85 (95% CI: 58.38, 73.32).This finding is in line with another meta-analysis that summarized the results of studies conducted in Africa, 67% [49].However, our estimate was higher than a previous meta-analysis conducted in Latin America and the Caribbean, 40.76% [9].This might be due to the marked difference in socio-economic status and healthcare services between the nations denoted in the primary studies [50].On the other hand, our prevalence estimate was lower than the finding of an earlier review that summarized the results of studies conducted in 17 sub-Saharan African countries, 77% [6].The possible explanation for this variation could be due to the difference in the study period of included studies; where, our analysis involved breast cancer patients diagnosed between 2005 and 2022 [33,42], while the sub-Saharan African analysis included breast cancer patients diagnosed between 1957 and 2012 [51,52]; and it is evidenced elsewhere that measures that reduce late-stage diagnosis like breast cancer screening had evolved over time [53].For example, the recent expansion of cancer care outside the national capital and the inauguration of the national cancer control strategy might contribute to this end [54].
The current review also identified determinants of late-stage diagnosis.Residence, patient delay, traditional medicine use and breast self-examination were found to have a statistically significant association with late-stage diagnosis.The risk of late-stage diagnosis was 92% higher among rural residents when compared to urban dwellers.This association was also detected by previous studies [55,56], and could be due to the lack of awareness and practice of early screening methods among rural dwellers [57,58].Poor access to preventive cancer care among rural residents could also be another elucidation for this variation [59].
In line with another study [60], this review indicated that breast cancer patients who had experienced patient delay for their first presentation were 2.65 times more likely to be diagnosed at an advanced stage than their counterparts.This might be due to the poor knowledge about signs and symptoms of breast cancer among delayed patients, thereby inhibiting timely consultation and leading to advanced disease stage [17].Similarly, patients who had utilized traditional medicine before diagnostic confirmation had a 2.54 times higher risk of late-stage diagnosis relative to their counterparts.The plausible explanation for this might be due to the progression of the disease with the lapses of time while receiving traditional medicine [16].
The present study showed that practicing breast self-examination reduces the risk of latestage diagnosis by 72%.This finding is supported by a previous study conducted in Togo [15].This might be because regular breast self-examination helps women to understand how their breast commonly feels, which in turn helps them to early notice changes in their breasts, and make them consult clinicians [61].The finding underlines the importance of regular breast self-examination in the early detection of breast cancer, particularly in resource-constrained settings like Ethiopia [62].Therefore, strengthening advocacy and integration of the breast self-examination education with outreach healthcare activities might help to reduce late stage diagnosis of patients.

Limitations of the review
Interpretation of the findings of this meta-analysis should be done with due consideration of the substantial heterogeneity between included studies.Studies that were published only in the English language were taken into account.Besides, variations in categorization between primary studies precluded the inclusion of some variables.

Conclusion
Two-thirds of breast cancer patients in Ethiopia were diagnosed at an advanced stage.Residence, delay in the first presentation, traditional medicine use and breast self-examination practice were significantly associated with late-stage diagnosis.Public education about breast cancer and its early detection techniques is crucial to reduce mortality and improve the survival of patients.Besides, improving access to cancer screening services is useful to tackle the disease at its curable stages.

Table 2 . Characteristics of included studies. First author & year of publication Study area Study design Data collection method Total participants Age in years Prevalence of LSD* Risk of bias
# : Median.https://doi.org/10.1371/journal.pone.0307283.t002